Systems for controlled release of biologically active compounds are known, e.g., those which contain a biologically active compound in a base of suitable biodegradable polymers such as polylactic acid or polyglycolic acid. For producing such systems, it is necessary to mix a biodegradable polymer with a biologically active compound, and then mold the mixture thus prepared into certain shapes, e.g., a rod-like, plate-like or spherical shape, etc. appropriate for respective intended ways of use. The procedures for molding the mixture into those shapes generally include either heat-melting the mixture and pouring it into a mold, followed by cooling and solidification, or dissolving the mixture in a solvent, pouring the solution into a mold, and then evaporating the solvent. However, high temperatures are required for heat-melting, i.e., 140-175° C. for DL-polylactic acid or polylactic acid/polyglycolic acid, and 190-220° C. for D- or L-polylactic acid. Many of biologically active compounds cannot withstand such high temperatures. Therefore, a method that includes a process of heat-melting of a mixture of a biologically active compound with polylactic acid or polyglycolic acid is not suitable as a general method for preparing a drug-releasing system. Also, in a method including a process of molding polylactic acid or polylactic acid/polyglycolic acid after dissolving them in a solvent, complete removal of the solvent from the molded product becomes necessary, which in general is very difficult, rendering such a method unsuitable as a general method for preparing a drug-releasing system.
On the other hand, Japanese Patent Application Publication S61-172813 describes a composite which is prepared by mechanically mixing a biologically active compound with DL-polylactic acid having a molecular weight of 1,000-5,000 or L- or D-polylactic acid having a molecular weight of 1,000, and heat-softening the mixture at 30-50° C. under the pressure of 200 kgf/cm2 (=1.96×103 N/cm2). Japanese Patent Application Publication No. S62-207227 discloses a releasing system which is prepared by heat treatment of poly(DL-lactic acid) (Mn=15,000) at 40° C. for 10 seconds under the pressure of 50 kgf/cm2 (=4.9×102 N/cm2).
However, in the method for preparing the systems described in these publications, it is typically DL-polylactic acid that is shown to be moldable without heating, according to what is described in the examples. Examples employing one of the optical isomers, D- or L-polylactic acid, alone are disclosed but they are limited to those having a very small molecular weight (1,000). As aforementioned, the melting point of polylactic acid differs depending on whether the polylactic acid is DL-, D- or L-form, among which also the softening temperatures naturally differ. The melting and softening points vary depending on the molecular weight; the greater the molecular weight, the more difficult it becomes to soften and melt. For example, a study performed by the present inventors using powder directly prepared by pulverizing L-polylactic acid having a weight-average molecular weight of over 3,000, its compression under room temperature caused no fusion of the particles, failing to give a molded product.
Upon this background, the objective of the present invention is to provide a method for production of a drug-releasing system containing polylactic acid and a biologically active compound, wherein the method requires neither heating nor solvent in the molding of the mixture of the biologically active compound and polylactic acid.